Ileum

Figure 9.9 Representation of the processes occurring along the gastrointestinal tract, and of the factors that must be taken into account in considering drug absorption.

15—20% of pool of bile salts to faeces

Figure 9.9 Representation of the processes occurring along the gastrointestinal tract, and of the factors that must be taken into account in considering drug absorption.

solution are absorbed from the gastrointestinal tract, colloidal particles, some viruses, bacteria and prion proteins can gain entry to the lymphatic system after absorption by specialised cells (M-cells) in the gut-associated lymphoid tissue (G ALT).3,4 A discussion of this route of uptake is outside the scope of this book, but it is a route which is likely to be increasingly explored as a means of developing proteins and perhaps genes in carrier nanoparticles and for oral vaccination.

9.2.2 Structure of the gastrointestinal tract

Figure 9.9(a) and (b) diagrammatically represents the gastrointestinal tract and some of the factors involved in the process of drug absorption from this complex milieu. The stomach is not an organ designed for absorption, the main site of absorption being the small intestine. The stomach may be divided into its two main parts: (i) the body of the stomach (a receptacle or hopper), which includes the pepsin- and HCl-secreting areas; and (ii) the pyloris (a churning chamber), the mucus-secreting area of the gastric mucosa. The stomach varies its luminal volume with the content of food and this is one reason why food intake can be so important in relation to drug absorption; the stomach may contain a few millilitres or a litre or more of fluid. Hydrochloric acid is liberated from the parietal cells at a concentration of 0.58%, or 160 mmol dm 3. The gastric glands produce some 1000-1500 cm3 of gastric juice per day. It is in this environment that pharmaceutical dosage forms find themselves. Some of the issues are shown in Fig. 9.9(b).

The small intestine is divided anatomically into three sections: duodenum, jejunum and ileum. Histologically there is no clearly marked transition between these parts. All three are involved in the digestion and absorption of foodstuffs, absorbed material being removed by the blood and the lymph. The absorbing area is enlarged by surface folds in the intestinal lining which are macroscopically apparent: the surface of these folds possess villi and microvilli (Fig. 9.10). It has been calculated that with a maximum of 3000 microvilli per cell in the epithelial brush border (so called because of its physical appearance) the number of microvilli in the small intestine mucosa, even of the rat, is 2 x 108 per mm2. Although one would expect organic acids to be absorbed only from the stomach where

Figure 9.10 Representation of the epithelium of the small intestine at different levels of magnification. From left to right: the intestinal villi and microvilli which comprise the brush border.

they will exist in the unionised lipid-soluble and membrane-diffusible form, the enormous surface area in the intestine allows significant absorption of acidic drugs from the intestine even though (as noted earlier) the fraction of unionised molecules is very small.

Over the entire length of the large and small intestines and the stomach, the brush border has a uniform coating (3 nm thick) of mucopolysaccharides which consist of multi-branched polymeric chains. This coating layer appears to act as a mechanical barrier to bacteria, cells or food particles, or as a filter. Whatever its function, the weakly acidic, sulfated mucopolysaccharides influence the charge on the cell membrane and complicate the explanations of absorption.

The goblet cells of the epithelium form mucus; secretions are stored in granule form in the apical cell region and are liquefied on contact with water to form mucus, which is composed of protein and carbohydrate.

The large intestine is concerned primarily with the absorption of water and the secretion of mucus to aid the intestinal contents to slide down the intestinal 'tube'. Villi are therefore completely absent from the large intestine, but there are deep crypts distributed over its surface.

Differences in the absorptive areas and volumes of gut contents in different animals are important when comparing experimental results on drug absorption in various species.5 The human small intestine has a calculated active surface area of approximately 100 m2. No analogous calculations are available for the most commonly used laboratory animals, although the surface area of the small intestine of the rat is estimated to be 700 cm2.

In discussing the pH-partition hypothesis, it has been considered that drugs are absorbed by passive diffusion through epithelial cells -the enterocytes of the GI tract for example. In fact there is the possibility of some passage of drugs by way of the tight junctions (the para-cellular route) and there are transcellular carrier-mediated uptake mechanisms as well as endocytosis. Figure 9.11 summarises these. The possibility of specialised membranous epithelial cells (M-cells) contributing to the uptake of macromolecules and proteins is referred to later.

9.2.3 Bile salts and fat absorption pathways

Fat is absorbed by special mechanisms in the gut. The bile salts which are secreted into the jejunum are efficient emulsifiers and disperse fat globules, allowing the action of lipase at the much increased globule surface. Medium-chain triglycerides are thought to be directly absorbed. Long-chain triglycerides are hydro-lysed, and the monoglycerides and fatty acids produced form mixed micelles with the bile salts and are absorbed either directly in the micelle or, more probably, brought to the microvillus surface by the micelle and transferred directly to the mucosal cells, the bile salts remaining in the lumen. The bile salts are reabsorbed in the ileum and transported via the portal vein back into the bile salt pool.

There have been suggestions that lipid-soluble drugs may be absorbed by fat absorption pathways. Certainly, administration of drugs in an oily vehicle can significantly affect absorption, increasing it in the case of griseo-fulvin and ciclosporin, but decreasing it in the case of vitamin D.

Paracellular Efflux

Transcellular Transcellular Endocytosis nwiYinnn pnpnn a^fvimnnii

Rinnnrn inn

Passive Carrier-mediated Specialised

Figure 9.11 GI membrane transport. Transport through the enterocyte barrier can be divided into active, passive and specialized transport; and into the paracellular and transcellular routes. Efflux mechanisms can reduce absorption by these routes.

9.2.4 Gastric emptying, motility and volume of contents

The volume of the gastric contents will determine the concentration of a drug which finds itself in the stomach. The time the drug or dosage form resides in the stomach will determine many aspects of absorption. If the drug is absorbed lower down the gut, the residence time will determine the delay before absorption begins; if the drug is labile in acid conditions, longer residence times in the stomach will lead to greater stability; if the dosage form is nondisintegrating then retention in the stomach can influence the pattern of absorption. Gastroretentive dosage forms are designed to achieve that control.

The stomach empties liquids faster than solids. The rate of transfer of gastric contents to the small intestine is retarded by the activity of receptors sensitive to acid, fat, osmotic pressure and amino acids in the duodenum and the small intestine and stimulated by material that has arrived from the stomach. Gastric emptying is a simple exponential or square-root function of the volume of a test meal - a pattern that holds for meals of variable viscosity. To explain the effect of a large range of substances on emptying, an osmoreceptor has been postulated which, like a red blood cell, shrinks in hypertonic solutions and swells in hypotonic solutions.

Acids in test meals have been found to slow gastric emptying; acids with higher molecular weights (for example, citric acid) are less effective than those, such as HCl, with very low molecular weights. Natural triglycerides inhibit gastric motility, linseed and olive oils being effective. The formulation of a drug may thus influence drug absorption through an indirect physiological effect. The nature of the dose form - whether solid or liquid, whether acid or alkaline, whether aqueous or oily -may thus influence gastric emptying. The question of gastric emptying and transit down the gastrointestinal tract has assumed further importance in relation to the design and performance of sustained-release preparations. The transit of pellets of different densities,6,7 for example, is shown in Fig. 9.12 and illustrates the influence of both density and food intake.

Food, then, affects not only transit but also pH. The effect of a meal on the hydrogen ion concentration of the stomach contents is shown in Fig. 9.13; the effect of two antacids on gastric volume and pH is shown in Table 9.4. When considering the effect of an antacid, therefore, the effect of volume change and pH change and the effect on gastric emptying must all be considered. In designing delivery systems all these factors have ideally to be taken into account.

Time (min)

Figure 9.12 Gastric emptying of pellets of different density with various sizes of meal.